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Jellbauer, Stephan (2009): The nucleolus: a nuclear compartment with impact on cytoplasmic mRNA localization. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The nucleolus is the most prominent subnuclear compartment in eukaryotic cells. It has a central function in the biogenesis of ribosomal subunits, but the past decade has revealed that a variety of additional non-ribosomal ribonucleoprotein (RNP) complexes require passage through the nucleolus during their maturation as well. Examples include small nuclear RNPs (snRNPs), the signal recognition particle (SRP), and viral RNPs. Recent data show that also specific localized messenger RNAs (mRNAs) or proteins implicated in their localization either reside predominantly in the nucleolus or accumulate there under certain conditions. This study presents evidence that two mainly nucleolar RNA-binding proteins of the yeast Saccharomyces cerevisiae, Loc1 and Puf6, influence the localization of ASH1 mRNA as well as the biogenesis of large ribosomal subunits. In addition, this study shows that block of nuclear mRNA export leads to accumulation of an RNA-binding protein crucial for localization of mRNAs, She2, and ASH1 mRNA in the nucleolus. Results in this thesis indicate that nuclear exclusion of She2 impairs translational regulation of ASH1 mRNA, a phenotype also observed for knockouts of LOC1 and PUF6. Detailed analysis of Loc1 function in this work demonstrates that it contributes to localization of other targeted mRNAs as well, that it does not directly inhibit translation of ASH1 mRNA and that it is involved in specific steps during biogenesis of the large ribosomal subunit. Data from truncation analysis and rapid depletion of Loc1 indicate coupling of its function in mRNA localization and ribosome biogenesis. Taken together, the results presented in this study suggest that nucleolar transit of localized mRNAs and of RNA-binding proteins such as She2 is necessary for proper translational control of localizing mRNPs. Loc1 might act in this process as an RNA chaperone, a function that could also explain its contribution to large ribosomal subunit biogenesis.